Preserved T-Cell Function in Children and Young Adults With Immune-Tolerant Chronic Hepatitis B

Institute of Cell and Molecular Science, Barts and The London School of Medicine & Dentistry, London, England.
Gastroenterology (Impact Factor: 16.72). 06/2012; 143(3):637-45. DOI: 10.1053/j.gastro.2012.06.009
Source: PubMed


Chronic hepatitis B (CHB) infection acquired perinatally or in early childhood has been associated with a prolonged phase of immune tolerance from viral exposure into early adulthood. The immune-tolerant phase of the disease is characterized by high levels of hepatitis B virus (HBV) DNA and normal liver biochemistry, with minimal or no fibrosis. We investigated whether the age of patients with CHB affects their antiviral immunity and whether children and young adults have a veritable state of immunologic tolerance.
We isolated T cells from different age groups of patients with CHB and used flow cytometric methods to measure production of effector and inflammatory cytokines (interferon, tumor necrosis factor, interleukin [IL]-17A, IL-22, and IL-8), T-helper (Th)2 cytokines (IL-10, IL-4), Th1 cytokines (IL-2 and IL-21), and the CC chemokine CCL3 (MIP-1). We also measured markers of T-cell exhaustion or inhibition (PD-1, LAG-3, TIM3, LAIR-1, and CTLA-4) and HBV-specific T cells.
Young patients with CHB have a Th1-cell cytokine profile and a partial profile of T-cell exhaustion. Direct quantification of the HBV-specific T-cell response showed that young patients with CHB have more HBV-specific T cells with the ability to proliferate and produce cytokines than adult patients with CHB.
HBV infection in younger patients is not associated with an immune profile of T-cell tolerance. On the contrary, children and young adults with chronic HBV infection have an HBV-specific immune profile that is less compromised than that observed in older patients.

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    • "A direct demonstration that the “immunotolerance” phase is not associated with an absence of virus-specific T cell immunity came directly from our recent study of chronic hepatitis B (CHB)-infected adolescents. Despite having a clinical and virological profile labeled as “immunotolerant,” these adolescents displayed a perfectly normal Th1 T cell response and harbored HBV-specific T cells that were actually functionally better than the ones detected in adult CHB patients in the “immune clearance” phase (36). "
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    • "In non-OLT HBV patients, analysis has revealed that HBsAg-positive newborns had higher regulatory T-cell frequencies and dysfunctional CD8 T cells, which represent immune tolerant status [122]. However, another report analyzing the immunological characteristics of HBsAg-positive young carriers and aged patients with active hepatitis revealed comparable peripheral T-cell proinflammatory cytokine production capacity and HBV-specific IFN-γ responses [123]. These findings indicate that tolerant carriers can react with HBV antigens and can show active immunity against HBV vaccination, if regulatory T-cell function diminishes. "
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    • "At this point, it is important to note that in contrast to adult-onset HBV infection more than 90% of newborns exposed to HBV at birth become persistently infected. However, a study performed by Kennedy et al.53 has suggested that chronic HBV infection in children is not associated with a compromised or tolerogenic T-cell profile suggesting that other mechanisms may contribute to the elevated rate of persisting HBV infection in children. "
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